A genetic variant in a PP2A regulatory subunit encoded by the PPP2R2B gene associates with altered breast cancer risk and recurrence

Authors

  • Alexei Vazquez,

    Corresponding author
    1. Department of Radiation Oncology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ
    2. The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ
    3. The Simons Center for Systems Biology, The Institute for Advanced Study, Princeton, NJ
    • The Cancer Institute of New Jersey, 120 Albany Street, New Brunswick, NJ 08963
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    • Tel.: 732-235-8918, Fax: 732-235-3952

  • Diptee Kulkarni,

    1. The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ
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  • Lukasz F. Grochola,

    1. Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, The University of Oxford, Old Rd Campus Research Building, Headington, United Kingdom
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  • Gareth L. Bond,

    1. Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, The University of Oxford, Old Rd Campus Research Building, Headington, United Kingdom
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  • Nicola Barnard,

    1. The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ
    2. Department of Pathology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ
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  • Deborah Toppmeyer,

    1. The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ
    2. Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ
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  • Arnold J. Levine,

    1. The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ
    2. The Simons Center for Systems Biology, The Institute for Advanced Study, Princeton, NJ
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  • Kim M. Hirshfield

    Corresponding author
    1. The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ
    2. Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ
    • The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08963, USA
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    • Tel.: 732-235-6028, Fax: 732-235-5331


Abstract

A recent candidate gene association study identified a single nucleotide polymorphism (SNP) in the PPP2R2B gene (rs319217, A/G) that manifests allelic differences in the cellular responses to treatment with chemotherapeutic agents (Vazquez et al., Nat Rev Drug Discov 2008;7:979-87). This gene encodes a regulatory subunit of protein phosphatase 2A (PP2A), one of the major Ser/Thr phosphatases implicated in the negative control of cell growth and division. Given the tumor suppressor activities of PP2A, here we evaluate whether this genetic variant associates with the age of diagnosis and recurrence of breast cancer in women. To investigate the linkage disequilibrium in the vicinity of this SNP, PPP2R2B haplotypes were analyzed using HapMap data for 90 Caucasians. It is found that the A variant of rs319217 tags a haplotype that appears to be under positive selection in the Caucasian population, implying that this SNP is functional. Subsequently, associations with cellular responses were investigated using data reported by the NCI anticancer drug screen and associations with breast cancer clinical variables were analyzed in a cohort of 819 Caucasian women. The A allele associates with a better response of tumor derived cell lines, lower risk of breast cancer recurrence, later time to recurrence, and later age of diagnosis of breast cancer in Caucasian women. Taken together these results indicate that the A variant of the rs319217 SNP is a marker of better prognosis in breast cancer.

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